It is highly desirable in many contexts that reproductive performance in mammals be improved or enhanced. For example, in farm animals, increased pregnancy rate and/or increased numbers of live offspring often would increase profitability. In meat-producing animals, increased litter size and birth or hatching rates improve the overall efficiency and profitability of a farm operation. Embryonic survival is directly relevant in avian species to improved hatching rates and for aquatic species to improved survival rate per spawn. Swine litter size would be positively influenced by the elimination of conditions that are lethal for developing embryos. Improved survival spreads the hatchery or piggery cost over a larger number of offspring, for example day-old chicks, post larvae shrimp, or piglets, and thus reduces the unit cost of production.
In milk producing animals, aside from the inherent value of young animals, periodic pregnancy and the resultant early lactation period are necessary or desirable for the animal to have steady and high milk yield. Tremendous efforts, such as systematic animal breeding programs and artificial insemination, have been and continue to be invested in ensuring that the animals have high and sustained productivity, and that the milk produced is of high quality or has desired composition.
While modern cattle breeding technologies have increased consistency of herd quality or performance and generally achieved increased milk yield, many studies have reported a decrease in fertility in dairy cows. Cows with the highest milk production have the lowest fertility performance. For example, it is well known that infertility is the major reason for culling cows, and it is estimated that in the UK alone, over 17,000 cows are culled every year due to infertility or reproductive failure (Genus Breeding, UK). Epidemiological studies suggest that, in addition to milk production, other factors such as increasing levels of inbreeding are probably decreasing reproductive efficiency in the dairy herd. The first-service conception rate declined approximately from 65% in 1951 to 40% in 1996 (Lucy, 2001, Reproductive loss in high-producing dairy cattle: where will it end? J Dairy Sci. 84:1277-93.). A large number of “normal embryos” in dairy cattle are found to undergo early embryonic death, but there is currently no explanation for such early embryo death. Reducing embryonic loss and achieving high rates of conception in dairy cattle would change the way we manage the lactation cycle (Lucy, 2001, supra).
The conception rate for cattle in the U.S. at first artificial insemination (AI) has also been decreasing for many years, and according to one report it decreased by 0.45% per year over a 20-year period (Butler and Smith, 1989, J. Dairy Sci. 72:767-83.). There was an increase in the number of AIs required for conception from 1.75 to more than 3 over a period of 20 years (Lucy, 2001, supra). Conception rates in large commercial herds stand at only 35-40% for mature cows. A similar need for improved reproductive performance exists with regard to many other farm animals such as swine, equine, sheep and goat.
In humans, infertility or low fertility plagues a significant portion of the population. It has been reported that in Western countries, about 10-15% of couples experience some difficulty with fertility (Evers, 2002, Female sub-fertility. Lancet 2:151-159.) Many couples suffering from impaired reproductive ability go to great effort and expense to successfully give birth to a child. The economic and emotional costs of embryonic mortality are significant, and a better understanding of its causes and improved methods for managing it are needed.
Infertility or low reproductive performance in animals, however, is presently poorly understood although it is known that there are many contributing factors, both genetic and environmental. It is nevertheless readily recognized that a genetic factor that causes the death of the embryo will be a major factor.
Lethal genes have been suggested as a cause of embryonic death and, if present, could cause failures in recurrent inseminations. However, lethal genetic factors or lethality genes if dominant, cannot survive in a population. Consequently, little is known about these lethal genetic factors. Identification and characterization of lethality genes would allow animal breeders, farmers and doctors to better understand low fertility, selectively improve the chances of success in animal breeding, develop strategic plans for improved fertility based on the genetics of parents and help eliminate these lethal factors from the population and improve overall reproductive performance in mammals.
As natural selection favors survival and reproduction of the more advantageous variants and elimination of the less advantageous variants, and an allele that confers lethality, even though recessive, generally decreases reproductive fitness of the individual carrying the lethality alleles. These recessive lethal alleles will eventually disappear from the population, unless it is otherwise selected for. Unnatural prevalence of a lethal allele, that is, at a frequency higher than predicted, indicates that it is favored by the condition under which the population is selected or propagated. Thus, if an allele is recessively lethal (reproductively disadvantaged), yet confers certain desirable production traits (for example, in the case of dairy cattle, milk yield or milk quality), this allele may be favored by breeding programs and persist in incidences higher than expected under natural selection conditions, even though its identity or phenotypic characteristics are not known. Insight about the exact nature of the phenotypic characteristics of recessive lethal alleles will be invaluable in assisting animal breeders in balancing reproductive performance with the animal's productive traits, and in achieving optimal economic outcome.